Some of the most innovative thinking on display at this year’s American Society of Clinical Oncology meeting came not from cancer companies, but from FDA and groups of oncologists and patient advocates who are busy rethinking how cancer drugs should be developed.
The meeting was chock-a-block with data readouts showing impressive response rates to innovative new therapies, and even included reports from one company taking an unquestionably novel tissue-agnostic approach to designing a clinical development program (see “Big Results in Small Cancers”).
But apart from a couple of brave explorers on the margins, biopharma companies have been slow to innovate in the way that clinical trials are done, preferring to tread well-worn pathways — even though most stakeholders agree the familiar approaches take too long, leave out too many patients and, as a result, fail to provide the information patients, physicians and payers need to make decisions.
FDA, ASCO and Friends of Cancer Research are among the groups leading industry down a path toward better data and better decision making, by using real-world evidence and expanding access to clinical trials to more patients.
FDA kicked the meeting off with an announcement that it would partner with ASCO to use its CancerLinQ database to track real-world outcomes for melanoma patients taking new drugs. The agency said information from the database could lead to label expansions.
In addition, during a session at ASCO that focused on looking at ways to supplement data from traditional randomized controlled trials, the agency encouraged companies to adopt the use of electronic medical records as a platform from which to conduct studies. FDA expects doing so would yield results that are more interpretable for patients and physicians in the real world, and could speed the enrollment and conduct of trials.
In a second session, the agency, ASCO and Friends of Cancer Research unveiled a set of recommendations for expanding enrollment in cancer trials to four populations who are usually excluded, including patients with brain metastases or HIV, children aged 12 and up, and patients with prior malignancies or organ damage. The hope is doing so would speed accrual of patients in trials while producing data that better reflect individuals who would actually take the drug.
While a small number of companies are leading the way in using basket trials to support approvals of drugs for molecularly defined cancers, FDA took the opportunity in a third session at ASCO to outline the conditions in which these studies are most useful.
REALIZING RWE
Regulators have been leading the charge to industrialize the use of real-world evidence (RWE) for premarket decision-making.
For instance, EMA’s adaptive pathway, which was created in 2014, allows for the use of real-world evidence to expand drug labels following approval for a narrow population based on randomized controlled trials.
In a review of the program last August, the agency noted that many of the companies that had applied to participate in a pilot program were denied because they lacked a clear vision of how they plan to incorporate real-world data into their development program.
FDA’s Center for Devices and Radiological Health (CDRH) has issued draft guidance on how RWE could be used to support device approvals, and the agency has committed to doing the same for drugs by 2021 under PDUFA VI.
Specifically, the 21st Century Cures Act and PDUFA reauthorization goals commit FDA to create a framework for the use of real-world evidence to satisfy the requirements for postapproval studies of drugs and to support approval of supplementary indications.
On June 1, FDA took another step down that path with the CancerLinQ announcement.
ASCO’s CancerLinQ includes structured and unstructured data captured from electronic medical records. The database currently has this information from 87 practices and cancer centers, covering over 500,000 patients.
“We have everything that’s in the EHR, from diagnoses to labs, to drugs administered to tumor-specific factors and so forth,” Robert Miller, medical director of CancerLinQ, told BioCentury.
Miller said the partnership will allow both FDA and ASCO to understand how new melanoma drugs, including checkpoint inhibitors and BRAF and MEK inhibitors, are being used in the real world.
“The collaboration will look at the clinical characteristics of those patients who receive them and what the outcomes are because what happens in the real world may or may not be different than what was seen in trials,” he said.
“The only concern is does that data set that the FDA received truly reflect what happened at the point of care.”
Sean Khozin, FDA
In a session at ASCO on June 2 titled “Moving Beyond the Randomized Controlled Trial: Real-World Data to Inform Patient Care and Policy,” Sean Khozin, acting associate director of FDA’s Oncology Center of Excellence, said the collaboration could help the agency gather safety data or efficacy data that could be used to expand the labeled indications for these newly approved therapies.
He also noted that companies could use platforms like CancerLinQ to address one of the short-comings of current randomized clinical trials — generalizability.
“We report results from a clinical trial in terms of average treatment effects, and this is what we’re urging our clinicians to make treatment decisions based upon. But in the clinic, I don’t think that I’ve ever seen a patient who falls in that median line. The result is that we have data that translates poorly into making individualized treatment decisions,” Khozin said.
He edged toward being more prescriptive when he said FDA thinks companies should begin to take advantage of electronic health/medical records. “Almost every doctor uses an electronic health record, and we can leverage these to capture the patient experience in real time,” Khozin said.
Doing so would allow companies to enroll more patients into clinical trials and could contribute to the generalizability of the results, he said.
He added that companies could conduct pragmatic trials of experimental agents where patients remain in their current practice setting but are entered into a trial and followed prospectively to track prespecified outcomes. These trials could be randomized at the practice, hospital or regional level.
“We can take clinical research to the patients and to the point of care, giving the physician the ability to offer the agent in a more controlled fashion,” Khozin said.
At the end of the session, a clinician raised the concern that doing studies in these less controlled settings make outcomes harder to predict. However, Khozin said the “integrity of controlled empiricism can be maintained by going to the point-of-care, if we do it correctly.” He didn’t elaborate.
He also hinted that data gathered via these platforms could be used to support approval of new drugs.
Without stating directly that traditional randomized control trials may not be necessary, Khozin said, “FDA doesn’t concern itself with where the data is coming from, whether it’s a case report form or an EMR.”
“The only concern is does that data set that the FDA received truly reflect what happened at the point of care, and we have an audit trail we can use to validate that,” he added.
After the session, Mark Rutstein, SVP of oncology at Bayer AG, told BioCentury the pharma does real-world studies to learn how patients and physicians use its drugs, and to generate data that could supplement pivotal trials in new indications. “There is great value in real-world evidence where you can answer a variety of questions, including different potential doses being used or to look at longer-term safety,” he said.
Bayer is conducting an observational study of its prostate cancer drug Xofigo radium-223 dichloride, which is approved to treat castration-resistant prostate cancer (CRPC). The pharma has found that physicians are using the drug in earlier lines of therapy and in combination with other drugs, including Zytiga abiraterone from Johnson & Johnson.
Bayer is running a Phase III trial of Xofigo in combination with Zytiga. The pharma expects the observational study will provide additional safety data for both the monotherapy and the combination in the real world.
“Randomized controlled trials allow us answer critical and important questions with a high degree of confidence, but it does not mean real-world evidence cannot complement this information,” Rutstein said.
OPENING THE GATES
While companies have merely been slow to innovate in RWE, they’ve been downright resistant to enrolling broader populations in their randomized controlled trials. In fact, industry has pushed hard in the opposite direction, narrowing trial entry criteria to accentuate efficacy signals.
FDA has gone on record saying companies should loosen exclusion criteria. Richard Pazdur, director of the Oncology Center of Excellence and of FDA’s Office of Hematology and Oncology Products, told BioCentury last year that companies need to be more flexible.
“What happens in the real world may or may not be different than what was seen in trials.”
Robert Miller, ASCO’s CancerLinQ
“We really want industry to focus on what things really matter in a trial, rather than just taking boilerplate language from one trial and applying it to another trial,” he said.
In a perspective in the April 20 New England Journal of Medicine, Pazdur and other FDA officials doubled down, calling for rational approaches to broadening clinical trial eligibility criteria. They noted specific populations are often excluded without a clear reason.
“Although the primary objective of eligibility criteria has been protecting patients, rational reconsideration of these criteria may lead to a more accurate description of a drug’s safety and efficacy in the patients who will ultimately receive the drug — and could expedite the development of prescribing information while maintaining safety,” they wrote.
According to ASCO, only 3% of cancer patients enter clinical trials, and as companies develop more agents targeting molecularly defined subgroups, this proportion could shrink. One of the major reasons for the lack of participation and slow accrual is the stringent enrollment criteria.
In a June 4 session titled “Strategies to Maximize Patient Participation in Clinical Trials,” FDA, ASCO and Friends of Cancer Research presented recommendations they said could speed accrual, increase patient participation and produce more generalizable results than clinical trials as they are run today.
While the complete list of companies who participated at the invitation of FDA, ASCO and Friends wasn’t disclosed at the session, Merck & Co. Inc. participated on the overall development of the recommendations and was on the pediatric working group.
The recommendations include routinely enrolling patients with treated and/or stable brain metastases. These patients are usually excluded because they have poor prognosis with shorter survival times that could mask a potential treatment benefit.
The recommendations also note there shouldn’t be an automatic exclusion for patients with new or progressive metastases. In these cases, companies should consider a patient’s disease history, the trial phase and design, and the drug mechanism and potential for CNS activity to determine eligibility.
Under the recommendations, patients with leptomeningeal disease would continue to be excluded because of safety concerns, unless there is evidence that the therapy under study may cross the blood-brain barrier.
FDA provided limited rationale for the recommendations, as they have yet to be published.
However, Julia Beaver, acting director of the Division of Oncology Products 1, said at the session that the main point was to “create a new culture of only excluding patients in situations where safety is warranted.”
Beaver was one of the authors of the NEJM perspective, which noted “including patients with brain metastases and excluding only those who currently have seizures or are taking medications with known drug interactions would permit initial examination of the study drug’s central nervous system (CNS) penetration and its related efficacy and safety.”
The group also tackled pediatric exclusions, which typically exist because of the challenges with identifying safe and effective doses in children as they continue to grow, and because the molecular pathology of tumors could be different in younger patients.
The recommendations call for dose-finding trials to include pediatric cohorts when there is strong scientific rationale based on the molecular pathways or histology and preclinical data. In later-phase trials for targets and indications that span adult and pediatric populations, patients 12 and older should be enrolled, and those under 12 should be considered, the group said.
A similarly liberal recommendation was made for HIV-positive patients, who have been excluded because these individuals used to be more susceptible to opportunistic infections and had poor prognoses before the availability of antiretroviral therapy.
The group recommended that HIV status should be treated the same as other co-morbidities and anti-retroviral therapy should be considered a concomitant medication. Patients with HIV infection who are healthy and at low-risk for AIDS-related outcomes should be included, and HIV-eligibility criteria should focus on current and past CD4 and T cell counts, history of AIDS-defining conditions and status of HIV treatment.
“We now have the availability of highly effective therapies for HIV and these individuals are living relatively normal lives and they’re living longer, which means that they’re developing cancer and we need to understand how these therapies work in these individuals,” said Jeff Allen, president and CEO at Friends.
In the case of patients with organ dysfunction, the group recommended that creatinine clearance could be ≥ 30 mL/min if there is limited renal excretion of the therapy. Additionally, the group felt that if there were no known cardiac risks, ejection fraction tests for cardiac health should be not be exclusionary, and ECG screening should be eliminated in later-phase trials.
Patients with previous malignancies should be permitted to enroll in trials if it’s been at least two years since there was evidence of disease, according to the recommendations.
REDUCING TO PRACTICE
FDA, ASCO and Friends have submitted the recommendations for publication, which is expected this year. FDA has no planned guidance on the topic and said it couldn’t require companies to follow the recommendations.
However, the agency said it would encourage companies to adopt less stringent criteria, and Beaver told BioCentury FDA would ask for scientific rationale if the old exclusions are used in future studies. The language on the label would also reflect that the agent was tested in a more narrow population.
“Incentives could be considered for sponsors that undertake these changes such as an expanded marketing claim if a new cohort that is traditionally excluded is added. Also, there could also be fewer postmarketing commitments. For example, the requirement to study use in patients with end organ damage could be omitted if these patients were included in the trials,” Beaver added.
Beaver also said FDA would take the expanded criteria into account when evaluating adverse events, and proposed at least two methods companies could use to prevent unexpected AEs or poor efficacy in these subpopulations from clouding a study’s results.
“It’s about getting a larger percent of the patients who experience the disease and potential benefit into the trial in the first place.”
Danelle James, Pharmacyclics
For early stage candidates, companies could study the drug in separate cohorts of these sicker and/or higher-risk patients groups. The design would be similar to basket studies where instead of looking at how a patient with a particular tumor type is responding, “you would look at different patient population cohorts such as a cohort with brain mets, a pediatric cohort, et cetera,” she said.
Basket trials have been used in cancer drug development to study an agent across multiple tumor types. The trial takes advantage of a single master protocol to enroll patients and includes prespecified criteria for when a cohort should be expanded based on early efficacy.
Alternatively, Beaver suggested companies could study an agent in a broad population in pivotal studies, but assess the primary endpoint in a narrower population that reflects the more traditional enrollment criteria.
Secondary endpoints would assess efficacy in the sicker and higher-risk populations, and the entire study population would be used to assess safety.
EARLY ADOPTERS
At least three companies are experimenting with expanded inclusion criteria.
For example, throughout the development program for lung cancer drug Tagrisso osimertinib, AstraZeneca plc included patients with brain metastases because over 40% of the population has them, and the pharma wanted to ensure the therapy would be useful for most patients.
“This was a situation where we looked at the population and we said how can we add on to that in a meaningful way,” said Andrew Coop, VP of U.S. medical affairs for oncology.
Tagrisso was approved in 2015 to treat EGFR-positive non-small cell lung cancer (NSCLC) that harbors the T790M mutation in patients who have progressed on or after treatment with an EGFR inhibitor. While Tagrisso’s label doesn’t mention its effects on brain metastases specifically, it does note that about 40% of patients in the Tagrisso clinical program had brain metastases.
Merck is running a Phase I trial of its PD-1 inhibitor Keytruda pembrolizumab in patients with HIV who have relapsed, refractory or disseminated cancers. Eric Rubin, VP of global clinical oncology, said there was a concern that PD-1 inhibition could make outcomes worse for HIV-infected patients. PD-1 blockade in HIV can cause systemic immune activation, leading to destruction of the immune system and disease worsening via systemic inflammation.
The trial is measuring the frequency of observed AEs as well as those associated with retroviral therapy and immune-related events. Rubin said early data suggest there are no safety concerns.
If final data are positive, he said Merck may revise enrollment criteria for other studies of Keytruda to include HIV-infected patients.
AbbVie Inc.’s Pharmacyclics unit relaxed the entry criteria for studies of its marketed drug Imbruvica ibrutinib, a Bruton’s tyrosine kinase (Btk) inhibitor.
According to Danelle James, head of clinical science at Pharmacyclics, the company decided to include patients with lower neutrophil and platelet counts based on the specificity of the drug and early clinical data that showed Imbruvica did not negatively impact these measures.
James said in trials to treat chronic lymphocytic leukemia (CLL) the cut-of for neutrophil counts was 2,000, well below the 50,000 cut-off that is typical.
“Having a more targeted agent allows you to broaden the more traditional eligibility criteria that is commonly excluded in leukemia and lymphoma,” she said. “We are trying to make our eligibility criteria as broad as the science will allow.”
The company also is enrolling adolescents over age 12 in its Phase III graft vs. host disease (GvHD) trial. “It’s about getting a larger percent of the patients who experience the disease and potential benefit into the trial in the first place,” James said.
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